This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Presequence peptidase (PreP) is a 117-kDa zinc metalloprotease that degrades amyloid-beta (A&#946;), a peptide implicated in Alzheimer?s disease. Additionally, PreP has been postulated to regulate mitochondrial targeting sequences after import into the matrix. Structural studies from the plant homolog, AtPreP, and homology modeling suggest that human PreP possesses an inner chamber (crypt) that may play a role in substrate selectivity. Coupled with biochemical studies, the suitability of this protease for therapeutic development towards Alzheimer?s disease will be greatly enhanced by structural studies that give an enhanced understanding of the mechanisms of how PreP selects and degrades its substrates.